Psychosocial stress is an important factor contributing to the onset of mood and anxiety disorders. Depression and anxiety disorders are more common in women than men, and there are important sex differences in responses to psychosocial stress. These data suggest that sex differences in responses to stress could mediate population-level sex differences in mental disorders. The social defeat paradigm reliably induces social withdrawal responses in animal models, a symptom that is present in both mood and anxiety disorders. However, a stumbling block to studying sex differences using this approach comes down to a simple problem. The most widely used rodent species have social organizations in which females are not aggressive towards each other. The basis for social defeat is physical confrontation. Thus, despite a steady drumbeat of ground breaking discoveries based on male mice and rats, there is a paucity of research on females. We study monogamous California mice, in which both males and females are aggressive. On average, females exposed to three episodes of social defeat show social withdrawal behavior whereas males do not. Kappa opioid receptors (KOR) function at the intersection of stress and depression-like behavior because they are activated during stress and can induce dysphoria. Studies in male mice suggest that the dysphoric effects of defeat stress are mediated in part by KOR activity. However, no study has ever tested this hypothesis in females. Preliminary data show that female California mice are, on average, more sensitive to the aversive properties of KOR than males. The proposed experiments test the hypothesis that sex differences in KOR activity contribute to sex differences in stress-induced social withdrawal. We also examine sex differences in KOR-dependent activation of p38 MAP kinase, which has been shown to mediate the aversive behavioral effects of KOR. The results of these experiments will provide novel insights into sex differences in the neurobiological and behavioral responses to social stress. Just in Time Information for 1R01MH097714-01A1 PI: Trainor, Brian C.